谷氨酰胺对烟雾吸入性肺损伤的保护效应及机制的实验研究
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摘要
研究背景
大面积烧伤后,机体免疫功能下降,对微生物的易感性明显增加,呼吸道成为全身感染的重要途径,尤其针对于烧伤合并吸入性损伤的患者。吸入性损伤是热力和(或)烟雾所致的呼吸道及肺实质的疾病,发病率和死亡率都很高。多发生于大面积烧伤,尤其是伴有头面部烧伤的患者。吸入性损伤是烧伤的主要死亡原因之一,以往的资料显示,吸入性损伤患者病死率一般在50%-60%,重度吸入性损伤的死亡率可高达90%。重度吸入性损伤可引起严重的急性肺损伤进而诱发急性呼吸窘迫综合征(ARDS)。尽管采用了新的通气技术和其他治疗措施,ARDS的死亡率仍高达40%-60%。因此,如何防止吸入性损伤患者的肺损伤的发生和发展引起了人们的高度重视,对于降低烧伤患者的死亡率尤为关键。吸入性肺损伤导致的急性肺损伤(acute lung injury, ALI)是一种失控的炎症反应,以肺血管内皮细胞及肺泡上皮细胞广泛损伤为特征,同时伴有肺出血、水肿和过度的炎症细胞浸润等特点。近年来的研究显示热休克蛋白(heat shock protein, HSP)对损伤或应激状态下机体具有保护作用,对急性肺损伤有一定的保护作用,可以减轻因氧化应激、炎症和缺血再灌注对肺的损伤,诱导或增强机体HSP的表达可能成为临床预防和治疗ALI/ARDS的新策略。
谷氨酰胺(Glutamine,GLN)是人体的条件必需氨基酸,也是人体内最丰富的游离氨基酸。在脓毒症和创伤等应激状态时,肠粘膜细胞以及快速增殖细胞(如免疫细胞),对谷氨酰胺的需求大大增加,而肺在短时间内释放出大量的谷氨酰胺。此后低浓度的谷氨酰胺,有可能导致肺的免疫功能失调和ARDS的发生。补充谷氨酰胺可以提高生存率、增强免疫功能、减少细菌感染、增强肠道屏障功能和防止肠道粘膜萎缩。最近研究显示用盲肠结扎手段造小鼠脓毒症模型后给予谷氨酰胺治疗,可明显降低TNF-α和IL-6的表达。研究显示静脉注射谷氨酰胺可使脓毒症大鼠的肺组织高度表达HSP70,起到抗内毒素休克的作用,降低了动物的死亡率。因此,谷氨酰胺可通过增强HSP70的表达多种类型的细胞损伤起到保护的作用。本研究通过建立大鼠烟雾吸入性损伤模型,同时给予谷氨酰胺来研究谷氨酰胺对大鼠烟雾吸入性肺损伤的保护效应及其机制。本研究分为三个部分。
第一部分烟雾吸入性损伤模型的建立
目的：烟雾吸入性损伤是严重烧伤患者引起急性呼吸衰竭的主要原因,在过去几年里烟雾吸入性损伤的治疗进展有限,为了进一步研究其发病机制,需要建立一种稳定、实用的烟雾吸入性损伤动物模型。
方法：将36只SD大鼠随机分为3组：每组12只,烟雾致伤时间分别是9min、12min、15min,随后观察7d生存率情况。每12h观察1次,并详细记录大鼠的死亡时间。将54只SD大鼠随机为2组：正常组(暴露在空气中,6只),对照组(烟雾致伤9min,48只),对照组设8个时间点,分别为伤后2h、4h、6h、24h、48h、96h、7d、及28d,每个时间点6只。测定血气分析、炎症因子、支气管肺泡灌洗液蛋白浓度及肺W/D比值。致伤后24h、96h、7d和28d后肺组织病理改变。致伤后7d及28d Masson染色。
结果：建立烟雾吸入性损伤模型,吸入浓烟造成缺氧和CO中毒。在我们的动物模型中发现肺组织明显的炎症反应,肺微血管通透性增强及中性粒细胞积聚。致伤24h后,HE染色显示：可见明显的肺水肿、弥漫性出血、肺泡间隔增宽和大量炎性细胞浸润,随着时间的延长,肺组织出现肺泡破裂,肺泡隔增厚,进一步损伤到肺实质。特别是致伤28d后肺组织胶原沉积,肺纤维化形成。
结论：大鼠烟雾吸入性损伤模型是一种稳定、实用、重复性好的动物模型,可用于急性和慢性肺损伤的实验。第二部分谷氨酰胺对烟雾吸入性肺损伤的保护效应研究
目的：烟雾吸入性损伤是与烧伤患者死亡率相关的一个重要原因。谷氨酰胺在危重患者和损伤中被认为是一种条件必需氨基酸,然而谷氨酰胺是否会对烟雾吸入性损伤起到保护作用仍然未知,本实验目的是探讨谷氨酰胺在烟雾吸入性肺损伤中的保护效应。
方法：54只大鼠随机分为以下3组(每组18只)：(1)正常组(吸入空气)；(2)对照组(烟雾吸入性损伤+生理盐水)；(3)实验组(烟雾吸入性损伤+谷氨酰胺)。将对照组和实验组的大鼠烟雾吸入造成吸入性肺损伤,实验组伤后30min经尾静脉注射谷氨酰胺溶液(750mg/kg),而对照组注射等体积的生理盐水。在伤后24h,3组各取6只大鼠,均过量麻醉(腹腔注射100mg/kg体重的戊巴比妥钠)后断头处死,取肺组织用于组织学及丙二醛(MDA)、超氧化物歧化酶(SOD)、TNF-α、IL-1β和IL-8的检测。每组剩余的12只大鼠用做生存率实验,观察周期为伤后4d,每12h观察1次,并详细记录大鼠的死亡时间。
结果：实验组大鼠生存率明显高于对照组(P<0.05)；烟雾吸入性损伤后大鼠肺组织MDA含量上升,而实验组肺组织MDA含量明显下降(P<0.01)；烟雾吸入性损伤后大鼠肺组织SOD活力下降,而实验组肺组织SOD活力明显上升(P<0.01)；同时,烟雾吸入性损伤后大鼠肺组织内TNF-α、IL-1β和IL-8含量分别上升,而实验组明显下降(P<0.01)；病理结果显示：谷氨酰胺减轻了烟雾吸入引起的肺水肿,弥漫性出血和炎性细胞浸润。
结论：谷氨酰胺可以明显减轻烟雾吸入导致的急性肺损伤,改善烟雾吸入性损伤的症状,改善肺的氧合功能,提高了大鼠的生存率,减轻了病理改变,防止肺水肿的发生,同时减轻了肺脏的氧化应激损伤和肺的急性炎症反应。证实了谷氨酰胺对烟雾吸入性肺损伤具有保护效应。
第三部分谷氨酰胺对烟雾吸入性肺损伤保护效应的机制研究
目的：探讨谷氨酰胺对烟雾吸入性肺损伤保护效应的可能机制。
方法：54只大鼠随机分为以下3组(每组18只)：(1)正常组(空气吸入,S组)；(2)对照组(烟雾吸入性损伤+生理盐水,C组),(3)实验组(烟雾吸入性损伤+谷氨酰胺,G组)。烟雾吸入性损伤后30min经尾静脉给予谷氨酰胺(750mg/kg),远期观察每日给药。时间点设3个时相点12h、24h和28d。测定支气管肺泡灌洗液中蛋白浓度及IL-8水平,动脉血气分析,肺W/D比值,肺组织HE和Masson染色,行肺组织HSP70、HO-1免疫组化检查,Western blot测定肺组织P-HSF-1、HSP70、HO-1、IκB-β及P-NF-κB p65的表达,行肺组织TUNEL染色及肺组织羟脯氨酸含量测定。
结果：动脉血气分析显示对照组和实验组的Pa02与正常组相比显著降低,而实验组的Pa02较对照组显著升高(P<0.01), PaCO2和pH值的变化实验组和对照组之间无显著差异；病理学评分显示实验组较对照组低(P<0.01)；实验组较对照组能够显著降低肺W/D比值和BLAF内蛋白浓度(P<0.01)；实验组较对照组肺组织TUNEL阳性细胞明显降低(P<0.01)；实验组BALF内IL-8水平与对照组相比显著降低(P<0.01); Western blot结果显示实验组肺组织P-HSF-1、 HSP70、HO-1、IκB-β的表达较对照组显著增加(P<0.01),而实验组肺组织P-NF-κB p65的表达较对照组显著降低；Masson染色和羟脯氨酸含量测定显示,实验组肺组织胶原沉积较对照组显著降低(P<0.01)。
结论：谷氨酰胺可以明显减烟雾吸入性肺损伤,减轻肺水肿,抑制炎症因子的释放,改善肺功能,减轻肺部病理改变,远期可抑制肺纤维化。谷氨酰胺可以减轻烟雾吸入所致的急性肺损伤,其保护作用机制可能与抑制炎症因子释放和提高热休克蛋白表达相关。
Background
As a result of extensive burns, the immune function decreases when susceptibility to microorganism increases significantly, and the respiratory track becomes the important route of general infection, especially to patients suffering the burn combined with the inhalation injury. The inhalation injury is a respiratory and pulmonary parenchymal disease caused by heat and (or) smoke. It usually occurs to patients suffering the extensive burn and especially the facial burn. It is one of the major reasons for death caused by burn. As revealed by data in the past, the case fatality rate of patients suffering the inhalation injury is generally between50%-60%, and it can reach as high as90%for patients with the severe inhalation injury, which can lead to the serious acute lung injury (ALI) and further induce the acute respiratory distress syndrome (ARDS). Although new ventilation technologies and other treatment measures have been applied, the fatality rate of ARDS still reaches as high as40%-60%. Thus, great attention has been paid to how to prevent occurrence and development of lung injury to patients suffering the inhalation injury, which is especially key to reduce the fatality rate of burn sufferers. ALI caused by the inhalation injury is an inflammatory reaction out of control. It is characterized by extensive injury of pulmonary vascular endothelial cells and alveolar epithelial cells and accompanied by pulmonary hemorrhage, edema, excessive inflammatory cell infiltration and other features. According to the researches in recent years, heat shock proteins (HSP) has the protective effect on the injured or stressed body and certain protective effect on ALI, and can alleviate injury to lungs caused by oxidative stress, inflammation and ischemia reperfusion, so it may be a new strategy for clinical prevention and treatment of ALI to induce or enhance the body HSP.
GLN is the richest free amino acid within the human body. In the stress state of sepsis and trauma, etc., the demand for GLN by intestinal mucosal cells and rapidly-proliferated cells (e.g. immune cell) increases greatly, and lungs will release a large amount of GLN within a short time. Afterwards, the low-concentration GLN may lead to pulmonary immune dysfunction and occurrence of ARDS. GLN supplement can promote the survival rate, enhance the immune function, reduce the bacterial infection, enhance the gut barrier function, and prevent atrophy of intestinal mucosa. As revealed by the recent researches, after GLN treatment is applied on the mouse sepsis model made through the means of caecum ligation, the expression of TNF-α and IL-6is reduced significantly. According to relevant researches, through intravenous injection of GLN, the lung tissue of a rat with sepsis can highly express HSP70to resist the endotoxin shock. In our present study,we produced the acute lung injury model by smoke inhalation and using the glutamine to investigate the protective of glutamine on smoke inhalation induced acute lung injury and its underlying mechanism.Our research was divided ino three parts.
Part One Building a rat model of smoke inhalation injury
Objective:Smoke inhalation injury is the leading cause of acute respiratory failure in critical burn victims. Advances in the treatment of smoke inhalation injury have been limited in the past years. To further explore the pathogenesis, stable and practical animal models are necessary; develop a rat model of smoke inhalation injury.
Methods:Part1,36rats were randomly divided into three groups:9,12, and15min based on the exposure time. The corresponding mortalities were recorded during the time exposure to smoke and the subsequent? days. Part2,54rats were randomly divided into two groups:normal group (ambient air exposure,6rats) and control group (9min time of smoke inhalation,48rats). After smoke inhalation, six rats were killed each time in the I group at2h,4h,6h,24h,48h,96h,7days and28days by overdosed pentobarbital sodium(100mg/kg body weight).The blood gas values, pro-inflammatory and protein concentration in bronchoalveolar lavage fluid and lung wet to dry weight ratio were assayed. Pathological evaluations of pulmonary were performed at24h,96h,7days and28days post-injury. Masson-Goldner trichrome staining was performed on day7and28post-injury.
Results:In our present animal model, smoke inhalation caused a significant hypoxemia and CO poisoning. A surge of pro-inflammatory response and microvascular hyperpermeability with neutrophils accumulations were also found in our animal model. At24h post-smoke inhalation, the hematoxylin and eosin results exhibited that there were inflammatory exudates and diffuse hemorrhage in the lung tissue with significant edema. With the time going, the lung injuries appeared at alveolar collapse and alveolar septum thickening, which indicated that smoke inhalation further induced damage to lung parenchyma. Specially, the markedly collagen deposition appeared at28days post-injury indicated that pulmonary fibrosis happened.
Conclusion:Rats model of smoke inhalation injury recommended in this article is a convenient, useful, stable and reduplicated animal model. Smoke generator could be used for acute and chronic lung injury experiments.
Part Two The therapeutic efficacy of glutamine for smoke inhalation-induced lung injury in rat
Objective:Smoke inhalation injury represents a major cause of mortality in burn patients and associated with a high incidence of pulmonary complications. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury.
Methods:Fifty-four rats were randomized into3groups:normal group (Sham operation), control group (Smoke inhalation injury+physiological saline) and experiment group (Smoke inhalation injury+Glutamine).The rat in control and experiment group were induced ALI by Smoke inhalation injury. The rats in the experiment groups were given glutamine solution750mg/kg body weight and the rats in control group were given saline at the same volume. At24h post-injury,6rats in each group were killed and their lung tissues were isolated and assayed for malonaldehyde (MDA), super oxide dismutase activity(SOD), TNF-α, IL-1β, IL-8and histological examination. The remained12rats in each group were used for monitoring the survival rate of mice every12h for4days
Results:Our experiments exhibited that the survival rate of experiments group was higher than control group (P<0.05).After Smoke inhalation injury, MDA content in the lung tissues was increased in the control group,whereas it was decreased in the glutamine treatment group (P<0.01). After Smoke inhalation injury, SOD activity in the lung tissues was decreased in the control group,whereas it was increased in the glutamine treatment group (P<0.01). After Smoke inhalation injury, TNF-α, IL-1β and IL-8content in the lung tissues was increased in the control group, whereas they were decreased in the glutamine treatment group. Glutamine treatment further attenuated lung edema inflammatory cell infiltrations, widened alveolar septum, and diffuse hemorrhage.
Conclusion:Our data demonstrated that Glutamine can relieve the acute lung injury induced by smoke inhalation, improve the symptoms of the lung injury induced by smoke inhalation and the oxygenation function of the lung, raise the survival rate of the rats, alleviate the pathologic change, prevent the development of pulmonary edema and alleviate the oxidative stress injury of the lungs as well as the acute inflammatory reaction of the lung. It proves that glutamine can exert protective effects on the lung injury induced by smoke inhalation.
Part Three The protective of glutamine on smoke inhalation induced lung injury and its underlying mechanism
Objective:The purpose of this study is to investigate the protective effects of glutamine treatment on smoke inhalation induced lung injury.
Methods:In our present work,54rats were equally randomized into three groups: normal group (Sham operation, ambient air inhalation), Control group (Smoke inhalation plus physiological saline) and experiment group (Smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and western blotting measurement.
Results:According to the arterial blood gas analysis, the PaO2of control group and experimental group is much lower than that of the normal group and the PaO2of the experimental group is much higher that of the control group (P<0.01). In terms of the changes of PaCO2and pH value, there is no obvious difference between the experimental group and control group. The pathological score of the experimental group is much lower than that of the control group (P<0.01). Comparing with the control group, the experimental group can reduce the W/D ratio and the protein concentration of BLAF significantly (P<0.01). The positive cell TUNEL of the lung tissue of the experimental group reduced obviously compared with the control group (P<0.01). The IL-8level in BALF of the experimental group is much lower than that of the control group (P<0.01). As the results of Western blot indicates, the P-HSF-1、HSP70、HO-1and IκB-β expression of the lung tissue of the experimental group increased evidently compared with that of the control group while the NF-κB expression of the lung tissue of the former reduced obviously compared with that of the latter(P<0.01). Masson stain and the hydroxyproline assaying show that the collagen deposition of lung tissue of the experimental group reduced evidently compared with that of the control group(P<0.01).
Conclusion:Glutamine can relieve the lung injury induced by smoke inhalation, mitigated pulmonary edema, obviously curb the release of the inflammatory factor, improve the pulmonary function, alleviate the pathologic change and curb the pulmonary fibrosis in long term. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSPs expression.
大面积烧伤后,机体免疫功能下降,对微生物的易感性明显增加,呼吸道成为全身感染的重要途径,尤其针对于烧伤合并吸入性损伤的患者。吸入性损伤是热力和(或)烟雾所致的呼吸道及肺实质的疾病,发病率和死亡率都很高。多发生于大面积烧伤,尤其是伴有头面部烧伤的患者。吸入性损伤是烧伤的主要死亡原因之一,以往的资料显示,吸入性损伤患者病死率一般在50%-60%,重度吸入性损伤的死亡率可高达90%。重度吸入性损伤可引起严重的急性肺损伤进而诱发急性呼吸窘迫综合征(ARDS)。尽管采用了新的通气技术和其他治疗措施,ARDS的死亡率仍高达40%-60%。因此,如何防止吸入性损伤患者的肺损伤的发生和发展引起了人们的高度重视,对于降低烧伤患者的死亡率尤为关键。吸入性肺损伤导致的急性肺损伤(acute lung injury, ALI)是一种失控的炎症反应,以肺血管内皮细胞及肺泡上皮细胞广泛损伤为特征,同时伴有肺出血、水肿和过度的炎症细胞浸润等特点。近年来的研究显示热休克蛋白(heat shock protein, HSP)对损伤或应激状态下机体具有保护作用,对急性肺损伤有一定的保护作用,可以减轻因氧化应激、炎症和缺血再灌注对肺的损伤,诱导或增强机体HSP的表达可能成为临床预防和治疗ALI/ARDS的新策略。
谷氨酰胺(Glutamine,GLN)是人体的条件必需氨基酸,也是人体内最丰富的游离氨基酸。在脓毒症和创伤等应激状态时,肠粘膜细胞以及快速增殖细胞(如免疫细胞),对谷氨酰胺的需求大大增加,而肺在短时间内释放出大量的谷氨酰胺。此后低浓度的谷氨酰胺,有可能导致肺的免疫功能失调和ARDS的发生。补充谷氨酰胺可以提高生存率、增强免疫功能、减少细菌感染、增强肠道屏障功能和防止肠道粘膜萎缩。最近研究显示用盲肠结扎手段造小鼠脓毒症模型后给予谷氨酰胺治疗,可明显降低TNF-α和IL-6的表达。研究显示静脉注射谷氨酰胺可使脓毒症大鼠的肺组织高度表达HSP70,起到抗内毒素休克的作用,降低了动物的死亡率。因此,谷氨酰胺可通过增强HSP70的表达多种类型的细胞损伤起到保护的作用。本研究通过建立大鼠烟雾吸入性损伤模型,同时给予谷氨酰胺来研究谷氨酰胺对大鼠烟雾吸入性肺损伤的保护效应及其机制。本研究分为三个部分。
第一部分烟雾吸入性损伤模型的建立
目的：烟雾吸入性损伤是严重烧伤患者引起急性呼吸衰竭的主要原因,在过去几年里烟雾吸入性损伤的治疗进展有限,为了进一步研究其发病机制,需要建立一种稳定、实用的烟雾吸入性损伤动物模型。
方法：将36只SD大鼠随机分为3组：每组12只,烟雾致伤时间分别是9min、12min、15min,随后观察7d生存率情况。每12h观察1次,并详细记录大鼠的死亡时间。将54只SD大鼠随机为2组：正常组(暴露在空气中,6只),对照组(烟雾致伤9min,48只),对照组设8个时间点,分别为伤后2h、4h、6h、24h、48h、96h、7d、及28d,每个时间点6只。测定血气分析、炎症因子、支气管肺泡灌洗液蛋白浓度及肺W/D比值。致伤后24h、96h、7d和28d后肺组织病理改变。致伤后7d及28d Masson染色。
结果：建立烟雾吸入性损伤模型,吸入浓烟造成缺氧和CO中毒。在我们的动物模型中发现肺组织明显的炎症反应,肺微血管通透性增强及中性粒细胞积聚。致伤24h后,HE染色显示：可见明显的肺水肿、弥漫性出血、肺泡间隔增宽和大量炎性细胞浸润,随着时间的延长,肺组织出现肺泡破裂,肺泡隔增厚,进一步损伤到肺实质。特别是致伤28d后肺组织胶原沉积,肺纤维化形成。
结论：大鼠烟雾吸入性损伤模型是一种稳定、实用、重复性好的动物模型,可用于急性和慢性肺损伤的实验。第二部分谷氨酰胺对烟雾吸入性肺损伤的保护效应研究
目的：烟雾吸入性损伤是与烧伤患者死亡率相关的一个重要原因。谷氨酰胺在危重患者和损伤中被认为是一种条件必需氨基酸,然而谷氨酰胺是否会对烟雾吸入性损伤起到保护作用仍然未知,本实验目的是探讨谷氨酰胺在烟雾吸入性肺损伤中的保护效应。
方法：54只大鼠随机分为以下3组(每组18只)：(1)正常组(吸入空气)；(2)对照组(烟雾吸入性损伤+生理盐水)；(3)实验组(烟雾吸入性损伤+谷氨酰胺)。将对照组和实验组的大鼠烟雾吸入造成吸入性肺损伤,实验组伤后30min经尾静脉注射谷氨酰胺溶液(750mg/kg),而对照组注射等体积的生理盐水。在伤后24h,3组各取6只大鼠,均过量麻醉(腹腔注射100mg/kg体重的戊巴比妥钠)后断头处死,取肺组织用于组织学及丙二醛(MDA)、超氧化物歧化酶(SOD)、TNF-α、IL-1β和IL-8的检测。每组剩余的12只大鼠用做生存率实验,观察周期为伤后4d,每12h观察1次,并详细记录大鼠的死亡时间。
结果：实验组大鼠生存率明显高于对照组(P<0.05)；烟雾吸入性损伤后大鼠肺组织MDA含量上升,而实验组肺组织MDA含量明显下降(P<0.01)；烟雾吸入性损伤后大鼠肺组织SOD活力下降,而实验组肺组织SOD活力明显上升(P<0.01)；同时,烟雾吸入性损伤后大鼠肺组织内TNF-α、IL-1β和IL-8含量分别上升,而实验组明显下降(P<0.01)；病理结果显示：谷氨酰胺减轻了烟雾吸入引起的肺水肿,弥漫性出血和炎性细胞浸润。
结论：谷氨酰胺可以明显减轻烟雾吸入导致的急性肺损伤,改善烟雾吸入性损伤的症状,改善肺的氧合功能,提高了大鼠的生存率,减轻了病理改变,防止肺水肿的发生,同时减轻了肺脏的氧化应激损伤和肺的急性炎症反应。证实了谷氨酰胺对烟雾吸入性肺损伤具有保护效应。
第三部分谷氨酰胺对烟雾吸入性肺损伤保护效应的机制研究
目的：探讨谷氨酰胺对烟雾吸入性肺损伤保护效应的可能机制。
方法：54只大鼠随机分为以下3组(每组18只)：(1)正常组(空气吸入,S组)；(2)对照组(烟雾吸入性损伤+生理盐水,C组),(3)实验组(烟雾吸入性损伤+谷氨酰胺,G组)。烟雾吸入性损伤后30min经尾静脉给予谷氨酰胺(750mg/kg),远期观察每日给药。时间点设3个时相点12h、24h和28d。测定支气管肺泡灌洗液中蛋白浓度及IL-8水平,动脉血气分析,肺W/D比值,肺组织HE和Masson染色,行肺组织HSP70、HO-1免疫组化检查,Western blot测定肺组织P-HSF-1、HSP70、HO-1、IκB-β及P-NF-κB p65的表达,行肺组织TUNEL染色及肺组织羟脯氨酸含量测定。
结果：动脉血气分析显示对照组和实验组的Pa02与正常组相比显著降低,而实验组的Pa02较对照组显著升高(P<0.01), PaCO2和pH值的变化实验组和对照组之间无显著差异；病理学评分显示实验组较对照组低(P<0.01)；实验组较对照组能够显著降低肺W/D比值和BLAF内蛋白浓度(P<0.01)；实验组较对照组肺组织TUNEL阳性细胞明显降低(P<0.01)；实验组BALF内IL-8水平与对照组相比显著降低(P<0.01); Western blot结果显示实验组肺组织P-HSF-1、 HSP70、HO-1、IκB-β的表达较对照组显著增加(P<0.01),而实验组肺组织P-NF-κB p65的表达较对照组显著降低；Masson染色和羟脯氨酸含量测定显示,实验组肺组织胶原沉积较对照组显著降低(P<0.01)。
结论：谷氨酰胺可以明显减烟雾吸入性肺损伤,减轻肺水肿,抑制炎症因子的释放,改善肺功能,减轻肺部病理改变,远期可抑制肺纤维化。谷氨酰胺可以减轻烟雾吸入所致的急性肺损伤,其保护作用机制可能与抑制炎症因子释放和提高热休克蛋白表达相关。
Background
As a result of extensive burns, the immune function decreases when susceptibility to microorganism increases significantly, and the respiratory track becomes the important route of general infection, especially to patients suffering the burn combined with the inhalation injury. The inhalation injury is a respiratory and pulmonary parenchymal disease caused by heat and (or) smoke. It usually occurs to patients suffering the extensive burn and especially the facial burn. It is one of the major reasons for death caused by burn. As revealed by data in the past, the case fatality rate of patients suffering the inhalation injury is generally between50%-60%, and it can reach as high as90%for patients with the severe inhalation injury, which can lead to the serious acute lung injury (ALI) and further induce the acute respiratory distress syndrome (ARDS). Although new ventilation technologies and other treatment measures have been applied, the fatality rate of ARDS still reaches as high as40%-60%. Thus, great attention has been paid to how to prevent occurrence and development of lung injury to patients suffering the inhalation injury, which is especially key to reduce the fatality rate of burn sufferers. ALI caused by the inhalation injury is an inflammatory reaction out of control. It is characterized by extensive injury of pulmonary vascular endothelial cells and alveolar epithelial cells and accompanied by pulmonary hemorrhage, edema, excessive inflammatory cell infiltration and other features. According to the researches in recent years, heat shock proteins (HSP) has the protective effect on the injured or stressed body and certain protective effect on ALI, and can alleviate injury to lungs caused by oxidative stress, inflammation and ischemia reperfusion, so it may be a new strategy for clinical prevention and treatment of ALI to induce or enhance the body HSP.
GLN is the richest free amino acid within the human body. In the stress state of sepsis and trauma, etc., the demand for GLN by intestinal mucosal cells and rapidly-proliferated cells (e.g. immune cell) increases greatly, and lungs will release a large amount of GLN within a short time. Afterwards, the low-concentration GLN may lead to pulmonary immune dysfunction and occurrence of ARDS. GLN supplement can promote the survival rate, enhance the immune function, reduce the bacterial infection, enhance the gut barrier function, and prevent atrophy of intestinal mucosa. As revealed by the recent researches, after GLN treatment is applied on the mouse sepsis model made through the means of caecum ligation, the expression of TNF-α and IL-6is reduced significantly. According to relevant researches, through intravenous injection of GLN, the lung tissue of a rat with sepsis can highly express HSP70to resist the endotoxin shock. In our present study,we produced the acute lung injury model by smoke inhalation and using the glutamine to investigate the protective of glutamine on smoke inhalation induced acute lung injury and its underlying mechanism.Our research was divided ino three parts.
Part One Building a rat model of smoke inhalation injury
Objective:Smoke inhalation injury is the leading cause of acute respiratory failure in critical burn victims. Advances in the treatment of smoke inhalation injury have been limited in the past years. To further explore the pathogenesis, stable and practical animal models are necessary; develop a rat model of smoke inhalation injury.
Methods:Part1,36rats were randomly divided into three groups:9,12, and15min based on the exposure time. The corresponding mortalities were recorded during the time exposure to smoke and the subsequent? days. Part2,54rats were randomly divided into two groups:normal group (ambient air exposure,6rats) and control group (9min time of smoke inhalation,48rats). After smoke inhalation, six rats were killed each time in the I group at2h,4h,6h,24h,48h,96h,7days and28days by overdosed pentobarbital sodium(100mg/kg body weight).The blood gas values, pro-inflammatory and protein concentration in bronchoalveolar lavage fluid and lung wet to dry weight ratio were assayed. Pathological evaluations of pulmonary were performed at24h,96h,7days and28days post-injury. Masson-Goldner trichrome staining was performed on day7and28post-injury.
Results:In our present animal model, smoke inhalation caused a significant hypoxemia and CO poisoning. A surge of pro-inflammatory response and microvascular hyperpermeability with neutrophils accumulations were also found in our animal model. At24h post-smoke inhalation, the hematoxylin and eosin results exhibited that there were inflammatory exudates and diffuse hemorrhage in the lung tissue with significant edema. With the time going, the lung injuries appeared at alveolar collapse and alveolar septum thickening, which indicated that smoke inhalation further induced damage to lung parenchyma. Specially, the markedly collagen deposition appeared at28days post-injury indicated that pulmonary fibrosis happened.
Conclusion:Rats model of smoke inhalation injury recommended in this article is a convenient, useful, stable and reduplicated animal model. Smoke generator could be used for acute and chronic lung injury experiments.
Part Two The therapeutic efficacy of glutamine for smoke inhalation-induced lung injury in rat
Objective:Smoke inhalation injury represents a major cause of mortality in burn patients and associated with a high incidence of pulmonary complications. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury.
Methods:Fifty-four rats were randomized into3groups:normal group (Sham operation), control group (Smoke inhalation injury+physiological saline) and experiment group (Smoke inhalation injury+Glutamine).The rat in control and experiment group were induced ALI by Smoke inhalation injury. The rats in the experiment groups were given glutamine solution750mg/kg body weight and the rats in control group were given saline at the same volume. At24h post-injury,6rats in each group were killed and their lung tissues were isolated and assayed for malonaldehyde (MDA), super oxide dismutase activity(SOD), TNF-α, IL-1β, IL-8and histological examination. The remained12rats in each group were used for monitoring the survival rate of mice every12h for4days
Results:Our experiments exhibited that the survival rate of experiments group was higher than control group (P<0.05).After Smoke inhalation injury, MDA content in the lung tissues was increased in the control group,whereas it was decreased in the glutamine treatment group (P<0.01). After Smoke inhalation injury, SOD activity in the lung tissues was decreased in the control group,whereas it was increased in the glutamine treatment group (P<0.01). After Smoke inhalation injury, TNF-α, IL-1β and IL-8content in the lung tissues was increased in the control group, whereas they were decreased in the glutamine treatment group. Glutamine treatment further attenuated lung edema inflammatory cell infiltrations, widened alveolar septum, and diffuse hemorrhage.
Conclusion:Our data demonstrated that Glutamine can relieve the acute lung injury induced by smoke inhalation, improve the symptoms of the lung injury induced by smoke inhalation and the oxygenation function of the lung, raise the survival rate of the rats, alleviate the pathologic change, prevent the development of pulmonary edema and alleviate the oxidative stress injury of the lungs as well as the acute inflammatory reaction of the lung. It proves that glutamine can exert protective effects on the lung injury induced by smoke inhalation.
Part Three The protective of glutamine on smoke inhalation induced lung injury and its underlying mechanism
Objective:The purpose of this study is to investigate the protective effects of glutamine treatment on smoke inhalation induced lung injury.
Methods:In our present work,54rats were equally randomized into three groups: normal group (Sham operation, ambient air inhalation), Control group (Smoke inhalation plus physiological saline) and experiment group (Smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and western blotting measurement.
Results:According to the arterial blood gas analysis, the PaO2of control group and experimental group is much lower than that of the normal group and the PaO2of the experimental group is much higher that of the control group (P<0.01). In terms of the changes of PaCO2and pH value, there is no obvious difference between the experimental group and control group. The pathological score of the experimental group is much lower than that of the control group (P<0.01). Comparing with the control group, the experimental group can reduce the W/D ratio and the protein concentration of BLAF significantly (P<0.01). The positive cell TUNEL of the lung tissue of the experimental group reduced obviously compared with the control group (P<0.01). The IL-8level in BALF of the experimental group is much lower than that of the control group (P<0.01). As the results of Western blot indicates, the P-HSF-1、HSP70、HO-1and IκB-β expression of the lung tissue of the experimental group increased evidently compared with that of the control group while the NF-κB expression of the lung tissue of the former reduced obviously compared with that of the latter(P<0.01). Masson stain and the hydroxyproline assaying show that the collagen deposition of lung tissue of the experimental group reduced evidently compared with that of the control group(P<0.01).
Conclusion:Glutamine can relieve the lung injury induced by smoke inhalation, mitigated pulmonary edema, obviously curb the release of the inflammatory factor, improve the pulmonary function, alleviate the pathologic change and curb the pulmonary fibrosis in long term. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSPs expression.
引文
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